Process for the stereoselective reduction of steroid enelactams

ABSTRACT

The novel process of this invention involves the reduction of certain  DELTA -5 steroidal alkenes to selectively produce either the 5 alpha  or 5 beta  reduction products. Particularly, this invention involves reduction of  DELTA -5 steroidal alkenes using a rhodium based catalyst in the presence of hydrogen to selectively yield 5 alpha  steroids or alternatively reduction of  DELTA -5 steroidal alkenes in an ionizing medium with a trialkylsilane to selectively yield 5 beta  steroids.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national phase application under 35 U.S.C. §371 ofPCT/US95/11355, filed Sep. 5, 1995, which is a continuation of U.S. Ser.No. 08/508,804 filed July 28, 1995, which issued to patent as U.S. Pat.No. 5,696,266, and which, in turn, is a continuation-in-part of U.S.Ser. No. 08/301,949 filed Sep. 7, 1994, which issued to U.S. Pat. No. as5,470,976.

FIELD OF THE INVENTION

The present invention is concerned with a novel process for thestereoselective reduction of enelactams. The process is particularlyuseful for the reduction of Δ-5 steroidal enelactams.

BACKGROUND OF THE INVENTION

The principal mediator of androgenic activity in some target organs,e.g., the prostate, is 5α-dihydrotestosterone ("DHT"), formed locally inthe target organ by the action of 5α-reductase, which convertstestosterone to DHT. Certain undesirable physiological manifestations,such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia(also called androgenetic alopecia) which includes female and malepattern baldness, and benign prostatic hyperplasia, are the result ofhyperandrogenic stimulation caused by an excessive accumulation oftestosterone ("T") or similar androgenic hormones in the metabolicsystem. Inhibitors of 5α-reductase will serve to prevent or lessensymptoms of hyperandrogenic stimulation in these organs. See especiallyU.S. Pat. Nos. 4,377,584, issued Mar. 22, 1983, and 4,760,071, issuedJul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that asecond 5α-reductase isozyme exists, which interacts with skin tissues,especially in scalp tissues. See, e.g., G. Harris, et al., Proc. Natl.Acad. Sci. USA, Vol. 89, pp. 10787-10791 (Nov. 1992). The isozyme thatprincipally interacts in skin tissues is conventionally designated as5α-reductase 1 (or 5α-reductase type 1), while the isozyme thatprincipally interacts within the prostatic tissues is designated as5α-reductase 2 (or 5α-reductase type 2).

The reduction of Δ-5 steroidal alkenes to the corresponding saturatedcompounds is an important step in the synthesis of steroid end-productsuseful as 5α-reductase inhibitors.

Platinum, palladium/carbon, and noble metals such as nickel have beenpreviously used as catalysts in the reduction of Δ-5 steroidalenelactams to preferentially yield the corresponding 5α-steriod. Thedegree of selectivity varies according to the particular steroidalenelactam being reduced. The best selectivity achieved using thesecatalysts to reduce 4,7β-dimethyl-4-aza-cholest-5-ene-3-one and its 4-NHanalog is about 100:1 of α:β product. Because the resulting α/β mixturecan be purified only with great difficulty, it was desirable to developa reduction process exhibiting greater selectivity for the α-reductionproduct. Furthermore, none of the previously described reductions,catalytic or otherwise, offered any way to selectively directhydrogenation to obtain the 5β reduction products which are also usefulas 5α-reductase inhibitors.

The instant invention provides an improved method for stereoselectivereduction of certain Δ-5 steroidal enelactams. In the case of4,7β-dimethyl-4 aza-cholest-5-ene-3-one, process parameters can beadjusted to preferentially yield the α-reduction product over theβ-reduction product in a ratio of about 500:1. The α-reduction productof 7β-methyl-4 aza-cholest-5-ene-3-one is selectively formed over theβ-reduction product in a ratio of about 264:1. Alternatively, theprocess parameters can be varied to selectively yield the β-reductionproduct of 4,7β-dimethyl-4 aza-cholest-5-ene-3-one and its 4-NH analogover the α-reduction products by ratios of about 60:1 and 90:1respectively.

SUMMARY OF THE INVENTION

The novel process of this invention involves the reduction of certainΔ-5 steroidal alkenes to selectively produce either the 5α or 5βreduction products. Particularly, this invention involves reduction ofΔ-5 steroidal alkenes using a rhodium based catalyst in the presence ofhydrogen to selectively yield 5α steroids or alternatively reduction ofΔ-5 steroidal alkenes in an ionizing medium with a trialkylsilane toselectively yield 5β steroids. This novel process can be exemplified inthe following embodiment. ##STR1## wherein R is selected from H and C₁-C₅ alkyl, R¹ is selected from C₁₋₅ alkyl and phenyl, and Z is ##STR2##

The α-reduction product corresponding to Formula II and the β-reductionproduct corresponding to Formula III are useful as 5α-reductaseinhibitors or as intermediates in the preparation of 5α-reductaseinhibitors. 5α-reductase inhibitors are useful in the treatment ofhyperandrogenic disorders such as benign prostatic hyperplasia, acnevulgaris, seborrhea, female hirsutism, androgenic alopecia (androgeneticalopecia), including male pattern baldness, and the prevention andtreatment of prostatic carcinoma.

DETAILED DESCRIPTION OF THE INVENTION

The novel process of this invention allows for greater stereoselectivecontrol than previously possible over the reduction of Δ-5 steroidenelactams.

Reduction of Δ-5 steroidal enelactams to 5α-steroidal lactams usingplatinum, palladium/carbon, and noble metals such as nickel catalysts isdescribed in U.S. Pat. No. 5,237,064, issued Aug. 17, 1993. The degreeof selectivity varies according to the particular steroidal enelactambeing reduced. The best selectivity achieved using these catalysts toreduce 4,7β-dimethyl-4 aza-cholest-5-ene-3-one and its 4-NH analog isabout 100:1 of α:β product. Because the resulting α/β mixture can bepurified only with great difficulty, it was desirable to develop areduction process exhibiting greater selectivity for the α-reductionproduct. The process of the present invention leads to stereoselectiveα/β ratio at least twice that of the prior reductions.

Acidic hydride reductions of various fused ring alkenes have beenreported in which one stereoisomer product predominates depending on thenature of the alkene substrate. Bulky silanes have been used to providehigh selectivity in the reduction of a non heteroatom stabilized alkene(octahydronaphthalene to decahydro-naphthalene), with the β productpredominating. See Doyle, M. P., McOsker, C. C., J. Org. Chem., 43(4),693-696 (1978). Acidic hydride reduction of enelactams, however, hasbeen reported to reduce ene-lactam with the 5α-product predominating.See, e.g., Rasmusson, et al., J. Med. Chem., 27, 1690 (1984); Rasmusson,et al., J. Med. Chem., 29, 2298 (1986); Jones, et al., J. Med. Chem.,36, 421 (1993); Cannon, et al., Synthesis, 494 (1986); and Murahashi, etal., J. Org. Chem., 2521 (1992). The process of the present inventionoffers a way to selectively obtain the 5β-reduction products of Δ-5steroid enelactams by exploiting the surprising discovery that, contraryto published reports, ionic reductions of enelactams favor β faceselectivity.

In one embodiment of this invention, a Δ-5 steroidal enelactam isdissolved in solvent and treated with H₂ in the presence of arhodium-based catalyst selected from Rh/Al₂ O₃ (5%) or Rh/C (5%) topreferentially obtain the α-reduction product.

In exemplifications of this invention where Rh/C (5%) is employed as thecatalyst, the solvent used is a C₁₋₆ alcohol, such as methanol, ethanol,n-propanol, isopropanol, etc. In particular, the preferred solvent inthe Rh/C catalyzed system is ethanol. When using Rh/Al₂ O₃ (5%) as thecatalyst, the solvent is a C₁₋₄ alkanoic acid, such as formic, acetic,propionic, or butyric acid. In particular, the preferred solvent in theRh/Al₂ O₃ catalyzed system is acetic acid.

Those skilled in the art are familiar with the use of catalytic amountsof reaction catalysts and will appreciate that the amount of catalystthat can be used may vary with the scale of the reaction. Generally, theamount of rhodium based catalyst used in the process of the presentinvention is adjusted so that the weight of rhodium present in thereaction mixture represents between 5-100% and preferably between 10-20%of the weight of the Δ-5 steroid alkene starting material. Inparticular, a weight of rhodium corresponding to about 20% of the Δ-5steroid alkene starting material weight is preferred.

The catalytic reduction is preferably run at a H₂ pressure of 40 psi,but pressure may be increased to as much as 250 psi in order to reducethe reaction time.

The rhodium catalyzed reduction can be optimally run between about20°-30° C. and may be conveniently run at room temperatures within thisrange. Temperatures above this range will adversely affect theselectivity of reduction and it is most preferable to maintain thereaction at the lower temperatures within this range.

A second embodiment of the present invention involves refluxing a Δ-5steroidal enelactam in an ionizing medium such as trifluoroacetic acidwith a trialkylsilane to preferentially yield the 5β-azasteroid product.Trialkylsilanes usable in the process of the present invention have theformula (R²)₃ SiH in which each alkyl group represented by R² may beindependently selected from C₁₋₆ alkyl and phenyl. In particular,trifluoroacetic acid is the preferred ionizing medium withdi-t-butylmethylsilane and tri-t-butylsilane being the preferredtrialkylsilanes usable in this embodiment of the invention.

The process of the present invention is useful for the stereoselectivereduction of Δ-5 steroidal enelactams. The process is particularlyuseful for the steroidal reduction of Δ-5 steroidal enelactams offormula I: ##STR3## wherein: is selected from H and C₁ -C₅ alkyl;

R¹ is selected from C₁₋₅ alkyl and phenyl, and Z is selected from##STR4##

The oxidation reaction is not affected by the substituent at the 16- or17-position of the steroid, and thus "A" can be any syntheticallyfeasible substituent. The flexibility and broad applicability of theinstant process is demonstrated by the fact that it is not limited bythe choice of substituent at the 16- and 17-positions of the steroidalstarting material.

Representative examples of "A" include but are not limited to: --H; keto(═O); protected hydroxy, e.g. dimethyl-t-butyl silyloxy,trimethylsilyloxy, tri-ethylsilyloxy, tri-isopropylsilyloxy,triphenylsilyloxy; acetate; hydroxy; carboxy, protected amino, e.g.acetylamino; amino; C₁₋₁₀ alkyl, e.g. methyl, ethyl, propyl, butyl,pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl cholestanyl 17-side chain,pregnane or stigmasterol 17-side chain; substituted or unsubstitutedC₁₋₁₀ alkenyl, e.g. phenylmethylene, chlorophenylmethylene,ethoxycarbonylphenylmethylene, carboxyphenylmethylene,(((1,1-dimethylethyl) amino) carbonyl)phenylmethylene, trimethoxyphenylmethylene, methoxyphenylmethylene, methylsulfonylphenylmethylene,biphenylmethylene, nitrophenylmethylene, aminophenylmethylene,acetylaminophenylmethylene, pivaloylaminophenylmethylene,phenoxyphenylmethylene, 2-imidazolyl methylene, 2-thiazolylmethylene;aryl substituted C₁₋₁₀ alkyl, e.g. omega-phenylpropyl,1-(chlorophenoxy)ethyl; aryl, e.g. phenyl, pyridinyl and pyrimidinyl;substituted aryl, e.g. phenyl, pyridinyl and pyrimidinyl substitutedwith one to three substituents independently selected from:

(1) --H,

(2) --OH,

(3) --CH₃,

(4) --OCH₃,

(5) --S(O)_(n) --CH₃, wherein n is selected from 0, 1, and 2,

(6) --CF₃,

(7) halo,

(8) --CHO,

(9) CN, and

(10) --NHR⁷, wherein R⁷ is selected from:

--H, --C₁₋₈ alkyl, --C₁₋₆ alkylcarbonyl, --C₁₋₆ alkylsulfonyl, and--C₁₋₆ alkoxycarbonyl, aryl carbamoyl substituted C₁₋₁₀ alkyl, e.g.2-(4-pyridinyl-carbamoyl)ethyl; C₁₋₁₀ alkylcarbonyl, e.g.isobutylcarbonyl; arylcarbonyl, e.g. phenylcarbonyl; ether-substitutedC₁₋₁₀ alkyl, e.g. 1-methoxy-ethyl, 1-ethoxy-ethyl; keto-substitutedC₁₋₁₀ alkyl, e.g. 1-ketoethyl, ketomethyl, 1-ketopropyl, and ketobutyl;heteroaryl-substituted C₁₋₁₀ alkyl, e.g. omega-(4-pyridyl)-butyl;carboxylic esters, e.g. C₁₋₁₀ alkylcarboxylic esters such ascarbomethoxy and carboethoxy; carboxamides, e.g. C₁₋₁₀ alkylcarboxamidesor aralkylcarboxamides such as N,N-diisopropyl carboxamide, N-t-butylcarboxamide, N-(hydroxyphenyl) carboxamide, N-phenylcarboxamide,N-(aminophenyl) carboxamide, N-(carbomethoxy)phenyl carboxamide,N-(methoxycarboxy) phenyl carboxamide,N-acetamidophenyl-N-acetyl-carboxamide, N-acetamidophenyl-carboxamide,N-pivalamidophenyl carboxamide, N-isobutyramidophenyl carboxamide,N-(methyl),N-(diphenylmethyl) carboxamide, andN-(diphenylmethyl)-carboxamide; carbamates such as C₁₋₁₀alkylcarbanates, especially t-butylcarbamate and isopropyl carbamate;substituted or unsubstituted anilide derivatives, e.g.N-substituted-phenyl-carboxamides wherein the phenyl may be substitutedwith 1 to 2 substituents selected from ethyl, methyl, trifluoromethyl orhalo (F, Cl, Br, I); C₁₋₁₀ alkanoyloxyC₁₋₂ alkyl, e.g. acetyloxymethyl,trimethylacetyloxy methyl, and (2-ethylhexanoyloxy)methyl; ureas, e.g.C₁₋₁₀ alkylcarbonylamino ureas such as t-butylcarbonylamino urea; C₁₋₁₀alkylureido C₀₋₅ alkyl, e.g., N-t-butylureidomethyl,N-n-propylureidomethyl, N-n-octylureidomethyl, N-isopropylureido,allylureido; substituted or unsubstituted arylureidoC₀₋₅ alkyl, e.g.,N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl,N-phenylureidomethyl, N-(dichlorophenyl) ureidomethyl,N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl,N-thien-2-ylmethylureidomethyl, N-(fluorophenyl)ureido,N-(methoxyphenyl)ureido, and 2-(ethoxyphenyl)ureidomethyl; C₁₋₁₀alkylcarbonylamino, e.g. t-butylcarbonylamino; alkanoylamidoalkyl, e.g.trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl,(isobutylphenyl)propionamidomethyl, 8-carboxyoctanoylamidomethyl,bromohexanoylamidomethyl, hydroxydodecanoyl amidomethyl,4-nitrophenylprionamidomethyl, isopropylthioacetamidomethyl,benzyloxyacetamidomethyl, carbometriphyacetamidomethyl,triphenylprionamidomethyl, cyclohexylacetamidomethyl, methylcyclohexanecarboxamidomethyl, (3-hydroxy-4,4,4-trichlorobutyramido)methyl, andphenylthio-acetamidomethyl; thioether, e.g. C₁₋₈ alkylthio, phenylthio,and C₁₋₈ alkylthio substituted with phenyl; ethers, e.g. n-butyloxy,ethylene ketal; substituted and unsubstituted aryl ethers such asthiophenoxy, biphenyloxy, (3-pyridyl)oxy, chlorophenyloxy,niethylphenyloxy, phenyloxy, methylsulfonylphenyloxy, pyrimidinyloxy;and the like.

Procedures for synthesizing compounds of structural formula (I) withvarious substituents at the 16- and 17- position are known in the art.The desired substitution at the 16- or 17- position may be effectedbefore conducting the stereoselective reduction of the presentinvention, or alternatively, some other substituent, such as hydroxyl orprotected hydroxyl may be present at the 16 or 17- substituent duringthe stereoselective reduction of the present invention, and subsequentto the reduction, the desired substitution may be effected on the D ringof the azasteroid.

Procedures for making ether and thioether substituents in the17-position are described in U.S. Pat. No. 5,091,534, and PCTPublications WO 93/23041 and WO 93/23040. 17-Anilide derivatives aredescribed, for example, in PCT publication WO 94/07861 and EP 0 663 924,and unsubstituted, monosubstituted or disubstituted amide derivatives inthe 17-position are described in PCT publications WO 93/23038, WO93/23051, WO 93/23420, and U.S. Pat. Nos. 4,220,775; 4,760,071;4,845,104; 5,237,067; 5,091,380; 5,061,801; 5,215,894.17-oxo-derivatives are described in U.S. Pat. Nos. 4,220,775; 4,377,584and 17-hydroxy derivatives are described in U.S. Pat. Nos. 4,220,775;4,377,584. Cyano derivatives at position 17 are described in U.S. Pat.No. 4,220,775 and 17-tetrazolyl analogs are described in U.S. Pat. No.4,220,775. 17-arylalkylcarbonyloxy alkyl derivatives,17-cycloalkylarylcarbonyloxy alkyl derivatives, and 17-benzoyloxyalkylderivatives are described in U.S. Pat. No. 4,377,584. 17-acyl,substituted or unsubstituted derivatives are described in U.S. Pat. Nos.5,049,562; 5,138,063; 5,151,429; 5,237,061; 5,120,742; 5,162,332;5,061,802; 5,098,908; 5,196,411; 5,075,450; 5,061,803; 5,324,734;17-thiobenzoyl are described in U.S. Pat. No. 5,151,430; and 17-polyaroyl derivatives are described in U.S. Pat. No. 5,162,322.Particular 17-alkyl derivatives, either substituted or unsubstituted,are described in PCT publications WO 93/23050, WO 93/23419, WO 93/23051and W095/00147 and 17-urea, thiourea, carbamate and thiocarbamatederivatives are described in PCT publications WO 93/23048; and 95/12398.

Procedures for substituting at position 16 with: lower alkyl isdescribed in PCT publication 93/23039, and U.S. Pat. Nos. 5,049,562;5,138,063; 5,278,159; and 4,377,584, and hydroxyl is described in U.S.Pat. Nos. 5,278,159 and 4,377,584. Procedures for further substitutionat position 17 are described in: PCT publication WO 95/11254.

Procedures for the formation of a 7-β bond are described in U.S. Pat.No. 5,237,064.

The term "alkyl" includes both straight and branched chain alkyl groups,and unless otherwise specified "aryl" includes phenyl, pyridinyl andpyrimidinyl.

Hydroxy and amino protecting groups are known to those of ordinary skillin the art, and any such groups may be used. For example, acetate,benzoate, ether and silyl protecting groups are suitable hydroxyprotecting groups. Standard silyl protecting groups have the generalformula --Si(Xa)₃, wherein each Xa group is independently an alkyl oraryl group, and include, e.g. trimethylsilyl, tri-ethylsilyl,tri-i-propylsilyl, triphenylsilyl as well as t-butyl-di-(Xb)-silyl whereXb is methyl, ethyl, isopropyl or phenyl (Ph). Standard amino protectinggroups have the general formula --C(O)--Xc, wherein Xc is alkyl, aryl,O-alkyl or O-aryl, and include, e.g. N-t-butoxycarbonyl. See alsoProtective Groups in Organic Synthesis, T. W. Green et al. (John Wileyand Sons, 1991) for descriptions of protecting groups.

One class of the process of the present invention comprises thereduction of a Δ-5 steroidal enelactams of formula I: ##STR5## wherein:Z is ##STR6## R is selected from H and C₁₋₅ alkyl; R¹ is selected fromC₁₋₅ alkyl and phenyl;

and A is any synthetically feasible substituent.

In a sub-class of this class of the invention, A is selected fromcarboxyl and hydroxyl. In a preferred embodiment of this subclass, R isselected from H and methyl and R¹ is methyl.

In yet another sub-class of this class of the invention, R is selectedfrom H and methyl, R¹ is methyl, and A is C₁₋₁₀ alkyl. In a preferredembodiment of this subclass, A is 6-methylhept-2-yl.

Another class of the process of the present invention comprises thereduction of a Δ-5 steroidal enelactams of formula I: ##STR7## wherein:z is ##STR8## R is selected from H and C₁₋₅ alkyl; R¹ is selected fromC₁₋₅ alkyl and phenyl;

and A is any synthetically feasible substituent.

In a sub-class of this class of the invention, A is selected from keto,hydroxyl, and protected hydroxyl. In a preferred embodiment of thissubclass, R is selected from H and methyl and R¹ is methyl.

In yet another sub-class of this class of the invention, A is selectedfrom ether and aryl ether. In a preferred embodiment of this subclass, Ris selected from H and methyl. Most preferably, R¹ is methyl.

Compounds of formula I are useful for making 7β-methyl substituted4-azasteroid compounds, and particularly those which are inhibitors of5α-reductase. Examples of such compounds include but are not limited tothose disclosed in U.S. Patent Nos. 4,377,594 and 4,760,071; WO93/23419; WO 93/23420; and WO 95/11254. More particularly, compoundsthat can be made from an intermediate of formula I in which Z is##STR9## and A is 6-methylhept-2-yl include those of general Formula IV:##STR10##

Synthesis of enelactams of formula I is described in U.S. Pat. No.5,237,064. An exemplary synthetic scheme showing how to make enelactamsof formula I and their subsequent reduction to compounds of formula II,compounds 8 and 9, is as follows: ##STR11##

The starting materials for the process generally are the3-acetoxy-androst-5-enes which are known and available in the art.

As shown in the above Reaction Scheme, the "Alk" substituent can beintroduced onto the B ring of the 4-aza steroid generally by theapplication of an organometallic carbonyl addition reaction, e.g., theGrignard reaction in which the 7-carbonyl group can be reacted with theGrignard reagent containing "Alk" as the R radical in RMgX. The Grignardreaction conditions are conventional and include the use of, e.g.,methyl, allyl or cycloalkyl magnesium chloride, ethyl magnesium bromide,cyclopropyl magnesium bromide, and the like. Preferably, the Grignardreagent is used with CeCl₃. Usable dry solvents include, e.g.,tetrahydrofuran (THF), diethyl ether, dimethoxyethane, and di-n-butylether. The reaction is conducted under dry conditions generally in thetemperature range of 0° C. to 40° C. Generally, the reaction requiresabout 6 to 24 hours for completion. Other organometallic carbonyladdition reactions can be used in this step, such as those utilizinglithium and zinc organometallic reagents which are known in the art."Alk" is C₁₋₅ alkyl or phenyl, preferably methyl, ethyl, butyl orphenyl.

The adduct 3 is then oxidized with e.g., aluminum isopropoxide andcyclohexanone (Oppenauer oxidation conditions) in, e.g., refluxingtoluene solvent to produce the 7-substituted-4,6-dien-3-one 4. Otherreagents which can be used are, e.g., aluminum ethoxide or aluminumt-butoxide. Other solvents which can be used include, e.g.,methylethylketone (MEK) and xylene. The temperature is generally in therange of about 60° to 120° C., and the reaction is carried out underanhydrous conditions and generally requires about 2 to 24 hours forcompletion.

The dien-3-one 4 is next converted to the 4-ene 5 by treatment with Pdon carbon, DBU (1,8-diazabicyclo 5.4.0!undecene-7, and cyclohexene in asolvent such as ethanol.

The A Ring is next cleaved by treatment with, e.g., potassiumpermanganate, sodium periodate in, e.g., t-butylalcohol at 80° C. toproduce the corresponding seco-acid 6. Other oxidation reagents whichcan be used include ruthenium tetraoxide and ozone. Other solvents whichcan be used are: CH₃ CN, CCl₄, methanol (MeOH) and CH₂ Cl₂. The reactiongenerally requires about 2 to 4 hours to proceed to completion.

The seco-acid in a C₂₋₄ alkanoic acid such as acetic acid (HOAc) istreated with ammonium acetate at about 15°-30° C. followed by warming toreflux for about 2 to 4 hours. After cooling to about 50-70° C., wateris added and the mixture seeded to cause crystallization of theene-lactam 7.

Hydrogenation of the ene-lactam to selectively obtain the 5α or5β-reduction product is accomplished described above and in the examplesthat follow.

If an N-alkyl compound of formula II is desired, lactam 8 may beN-alkylated as illustrated in Example 2. Alternatively, an N-alkylatedenelactam of formula I prepared according to the methods outlined inU.S. Pat. No. 5,237,064, may be directly reduced by the process of thisinvention as illustrated in Example 3.

Both the 4-N-alkyl and the 4-NH enelactams are unstable in air and thesolvent should be degassed prior to dissolving the enelactam andsubsequent reduction. In the case of the 4-NH enelactam, an amount ofBHT (butylated hydroxy toluene) corresponding to 0.2% of the startingmaterial should also be added to the solvent before dissolving theenelactam.

Representative experimental procedures utilizing the novel process aredetailed below. These procedures are exemplary only and should not beconstrued as being limitations on the novel process of this invention.

EXAMPLE 1 Preparation of 7β-methyl-4-aza-5α-cholestan-3-one

Step 1

    ______________________________________                                         ##STR12##                                                                     ##STR13##                                                                    Materials        Amt           Mole  MW                                       ______________________________________                                        Cholesteryl acetate                                                                            78.1   g      0.173 428.7                                    (95% Aldrich)                                                                 t-BuOOH          189    g      1.46  90.12                                    (70 wt %, Aldrich)                                                            Na.sub.2 WO.sub.4 2H.sub.2 O                                                                   3.3    g      0.010 329.9                                    RuCl.sub.3 xH.sub.2 O                                                                          0.24   g      0.00116                                                                             207.43                                   Sodium metasilicate                                                                            0.315  g      0.00258                                                                             122.06                                   (Na.sub.2 SiO.sub.3)                                                          Sulfuric acid    0.45   mL     0.0081                                                                              98.08                                    (d = 1.84 g/mL, 18M)                                                          Sodium sulfite (Na.sub.2 SO.sub.3)                                                             39     g      0.309 126.04                                   heptane          300    mL                                                    MEK (methyl ethyl ketone)                                                                      550    mL                                                    water            460    mL                                                    ______________________________________                                    

In a 2000 mL 3-necked flask was added sodium tungstate dihydrate (3.3g), sodium metasilicate (0.315 g) and 70 mL water and stirred untilhomogeneous. The solution was neutralized (pH=6-7) with concentratedsulfuric acid (0.45 mL). A 4° C. exotherm was noted for the addition ofacid. Ruthenium trichloride hydrate (240 mg) was added and the mixturestirred for 10 min. Cholesteryl acetate (78.1 g) and heptane (300 mL)were added to the catalyst mixture. The stirring rate was 225-275 rpmwith an overhead paddle stirrer.

70% t-BuOOH (189 g) was added over 5-10 min. An internal temperature of15°-20° C. was maintained by cooling with a water bath. The temperatureof the batch began to rise slowly after an induction period of 5-15 min.The reaction was stirred until less than 1.5 wt % of s.m. (startingmaterial) and less than 2% of the 7-hydroxy cholesteryl acetateintermediate remained, about 20-24 hrs.

The reaction was monitored with a YMC basic column, 90:10acetonitrile:water, flow rate=1.5 mL/min, UV detection at 200 nm.Retention times: t_(R) cholesteryl acetate=17.0 min, t_(R) 7-ketocholesteryl acetate=7.8 min, t_(R) enedione 4.5 min, t_(R)7-hydroperoxides, 7-ols intermediates=6.8, 6.9, 7.0, 8.2 min. Latereluting impurities at 18 and 19 min are the 7-t-BuOO-cholesterylacetates.

To the reaction mixture was added 550 mL MEK, 390 mL water, and 39 gsodium sulfite. The mixture was heated to 70° C. until the enedioneimpurity was gone, about 3 hrs. The reaction mixture cooled, then wastransferred to a separatory funnel and the aqueous layer cut and thenthe organic layer washed with 100 mL 1% brine. The MEK and t-BuOH werethen removed by an azeotropic distillation with heptane (900 mL heptaneadded after an initial concentration to 300 mL) until less than 0.7%combined MEK and t-BuOH remained as assayed by GC (gas chromatography).

The heptane was checked for MEK and tBuOH levels by GC using an HP-5column at 35° C. with a 0.5 mL flow rate. t_(R) MEK=4.9 min, t_(R)tBuOH=5.3 min, t_(R) heptane=7.7 min. The volume was adjusted to 350 mL,cooled to -5° C. and filtered, washing twice with 150 mL 0° C. heptane.After drying, the product was obtained as an off-white solid. Meltingpoint (m.p.): 155°-157° C. NMR (¹ H, 300 MHz, CDCl₃): 5.70 (s, 1H), 4.7(m, 1H), 2.5-0.3 (m, 43H), 0.6 (s, 3H).

Step 2

    ______________________________________                                         ##STR14##                                                                     ##STR15##                                                                    Materials          Amt        Mole   MW                                       ______________________________________                                        7-keto-cholesteryl acetate (95% pure)                                                            60     g (as is)                                                                             0.13 442                                    Methyl magnesium chloride (3.0M)                                                                 160    mL      0.48                                        CeCl.sub.3 (anhydrous)                                                                           16.6   g       0.068                                                                              245                                    THF (KF = 50 μg/mL)                                                                           300    mL                                                  Citric acid        115    g       0.60 192                                    water              500    mL                                                  toluene            600    mL                                                  sat'd NaHCO.sub.3  240    mL                                                  ______________________________________                                    

Anhydrous cerium chloride (16.6 g) was stirred as a slurry in THF (150mL) at 20° C. under N₂ for 2h. After two hours a sample of the slurrywas removed and showed fine needles under a microscope. To the slurrywas added the Grignard reagent (160 mL) and the resulting light purplemixture was aged for 30 minutes.

To the cooled mixture (20° C.) was added the ketone (60 g at 95% purity,57 g by assay) in THF (150 mL) over 50 minutes while allowing themixture to exotherm to 30° C. Addition of the ketone to the Grignardreagent was exothermic, the exotherm was controlled by the rate ofaddition. The ketone solution in THF should be warmed to 30° C. toensure complete dissolution, prior to adding it to the Grignard reagent.

The reaction progress was monitored by HPLC (high pressure liquidchromatography). A 0.5 mL sample was added to 10 mL of 0.1N HOAc andthen diluted to 50 mL with CH₃ CN. HPLC conditions Zorbax® phenylcolumn, CH₃ CN, water, phosphoric acid; 75:25:0.1 gradient elution to90:10:0.1 at 18 minutes, flow=1.5 mL/min, UV detection at 200 nm!.Retention times, 3,7-diol t_(R) =5.6 and 5.9 min, starting ketone t_(R)=10.9 min, intermediate 7-OH, 3-OAc t_(R) =9.8 and 10.8 min.).

Once complete, the reaction was quenched by adding it to a 0° C. mixtureof citric acid solution (115 g in 300 mL of water) and toluene (300 mL).The quench was exothermic. (NOTE: The rate of addition should becarefully controlled to maintain an internal temperature below 10° C.)

The two phase mixture was stirred for 30 minutes and allowed to standfor 10-15 minutes for an adequate phase separation. The pH of theaqueous layer was ca. 2. The organic phase was separated, washed withwater (200 mL, pH=3 after washing) and saturated NaHCO₃ solution (240mL, pH=8 after washing). This afforded 750 mL of an organic layer whichcontained 66 mg/mL of diol.

The batch was concentrated to 300 mL in vacuo (100-200 mm), diluted to600 mL with toluene and re-concentrated to 360 mL. The solvent switch totoluene was considered complete when the G.C. area % of THF was <2% ofthe toluene area %. (NOTE: The first 200 mL of the distillation has atendency to foam at low pressures. Once this phase is complete, thevacuum should be brought down to 100 mm. The distillation temperatureslowly rises from 20° C. to ca. 45° C. as the solvent switch to toluenenears completion.)

Samples of the distillate were assayed for residual THF using G.C. Asample of ca. 0.1 mL was diluted to 1 mL with methanol. G.C. conditions:HP-5 column (25M, 0.32 μm ID) using a heated block injector, 35° C.isothermal, flow=0.5 mL/min!, MeOH t_(R) =5.5 min, THF t_(R) =6.2 min,toluene t_(R) =10.1 min. The final assay was performed using a samplefrom the batch.

The organic layer contained 134.4 mg/mL of diols. (NOTE: The KF of thebatch should be below 100 μg/mL before proceeding with the next step.)

Step 3 Oppenauer Oxidation

    ______________________________________                                         ##STR16##                                                                     ##STR17##                                                                     ##STR18##                                                                    Materials         Amt       MMole    MW                                       ______________________________________                                        7-methyl-7-hydroxy-cholesterol                                                                  30.2    g     72.6   416                                    2-butanone (d = 0.805, KF = 480                                                                 126     mL    1404   72.11                                  μg/mL)                                                                     Aluminum isopropoxide                                                                           18.9    g     93                                                              204.25                                                      3N HCl            120     mL                                                  5% NaCl solution  120     mL                                                  Conc. HCl         3.5     mL    42                                            D.I. water        60      mL                                                  Saturated NaHCO.sub.3                                                                           60      mL                                                  ______________________________________                                    

To the toluene solution of the diol (256 mL, 118 mg/mL) was added2-butanone (126 mL) and aluminum isopropoxide (18.9 g). The solution washeated to reflux (92° C.) under nitrogen. The reaction progress wasmonitored by HPLC.

The batch was assayed for 2-butanone content by G.C. prior to adding thealuminum isopropoxide. A sample of ca. 0.1 mL was diluted to 1 mL withMeOH. G.C. conditions HP-5 column (25 m, 0.32 μm ID) using a heatedblock injector at 250° C., column temp at 35° C. isothermal, flow=0.5mL/min! 2-butanone t_(R) =6.1 min, MeOH t_(R) =5.5 min, toluene t_(R)=10.1 min. The KF of the starting mixture was 70 μg/mL.

A 0.1 mL sample of the reaction mixture was quenched into 0.1N HOAcsolution (2-3 mL) and then diluted to 10 mL with CH₃ CN in a volumetricflask. HPLC conditions 25 cm Zorbax® Phenyl column; CH₃ CN:H₂ O with0.1% phosphoric acid: 75:25 gradient elution to 90:10 at 18 min, hold90:10 until 22 min; flow=1.5 mL/min, UV detection at 210 nm.! Startingdiols t_(R) =5.4, 5.9 min, intermediate Δ-4 eneone t_(R) =6.4 min,dieneone t_(R) =12.1 min.

The reaction was considered complete when the level of starting diol was<3 area % (8 hours). Once complete the batch was cooled to 15°-20° C.and quenched with 3N HCl (120 mL). The two phase mixture was stirred for20 min, and then allowed to settle. The lower aqueous layer was removedand the organic layer was washed with 5% NaCl (120 mL). The batch wasconcentrated in vacuo to one half volume (40-60° C. at 150 mm). Thedistillation removed excess 2-butanone from the batch. The level of2-butanone in the final batch was <2% of the toluene (using G.C.) andthe KF was 60 μg/mL.

The toluene solution was treated with conc. HCl (3.5 mL) at 25° C.,under N₂. The reaction was assayed by HPLC until the intermediatetertiary alcohol was completely converted to dieneone (about 1 h). Thesolution was washed with D.I. water (60 mL) and saturated NaHCO₃ (60mL). The pH of the bicarbonate wash was 8.5. (NOTE: The decompositionreaction will turn black if run for longer than 8 hours.) The resultingred solution (128 mL) contained 202 mg/mL of dienone.

Step 4 Transfer Hydrogenation

    ______________________________________                                         ##STR19##                                                                     ##STR20##                                                                    Materials         Amt      MMole    MW                                        ______________________________________                                        Dieneone (toluene solution)                                                                     31.5   g     79.5   396.7                                   5% Palladium on carbon (dry)                                                                    4.5    g                                                    Cyclohexene(d = 0.811)                                                                          120    mL    1.18 mole                                                                            82.15                                   1,8 diazabicyclo 5.4.0!undec-7-ene                                                              0.63   mL    4.2    152.2                                   (DBU)                                                                         Absolute ethanol  495    mL                                                   3N HCl            150    mL                                                   half saturated NaHCO.sub.3                                                                      100    mL                                                   Solka Floc ™ diatomaceous earth                                            Hexanes           250    mL                                                   t-butanol         175    mL                                                   ______________________________________                                    

The toluene solution of the dieneone (150 mL at 214.6 mg/mL) was dilutedwith ethanol (120 mL) and cyclohexene (120 mL) and DBU (0.62 mL). To themixture was added 5% palladium on carbon (9.0 g of 50% water wet). Themixture was degassed using vacuum/nitrogen purges (3×). The slurry wasthen heated to reflux (reflux temperature=72° C.). The reaction wasmonitored by HPLC.

A 2 mL sample of the reaction mixture was filtered through Solka Floc™diatomaceous earth. The filtrate (0.1 mL) was diluted to 10 mL with CH₃CN and analyzed by HPLC: 25 cm Zorbax® phenyl column; acetonitrile/watercontaining 0.1% phosphoric acid: gradient elution from 75:25 to 90:10CH₃ CN:water in 18 min, hold 90:10 until 22 min; flow=1.5 mL/min; UVdetection at 200 nm.

Dienone t_(R) =12.1 min, Δ-4 enone t_(R) =13.2 min, Δ-5 enone t_(R)=14.1 min, over-reduced ketone t_(R) =14.4 min, ethyl enol ether t_(R)=20.9 min. The over-reduced ketone should be assayed at 192 nm.

The reaction was considered complete when the dieneone level was <2 A%and the Δ-5 enone level was 5% (about 10 hours). When the reaction wascomplete the mixture was cooled to ambient temperature. The palladiumwas removed by filtration through Solka Floc™ diatomaceous earth and thefilter cake was washed with ethanol (150 mL).

The batch contained 51 mg/mL of enone. (NOTE: Prolonged reaction timesshould be avoided since over-reduction can occur. If the startingmaterial has been consumed and the level of Δ-5 enone is >5% after 10hours, then the palladium should be filtered, and the isomerizationcompleted without catalyst present.)

The solution was concentrated under reduced pressure (75 mm) to a volumeof approximately 150 mL. The batch was diluted with ethanol (225 mL) andre-concentrated to 150 mL.

The solvent switch to ethanol was considered complete when the toluenelevel was <2% of the ethanol by G.C., and there was no detectablecyclohexene. (NOTE: Removal of cyclohexene is important since it reactsin the subsequent oxidative cleavage step and unproductively consumesperiodate.) A 0.1 mL sample was diluted to 1 mL with ethanol for thecyclohexene assay (and 1,1,1 trichloro-ethane for the toluene assay).G.C. conditions HP-5 (25M ×0.32 μm ID), using a heated block injector at250° C., column temp at 35° C. isothermal, flow=0.5 mL/min! ethanolt_(R) =5.6 min, cyclohexene t_(R) =7.7 min, trichloroethane t_(R) =7.7min, toluene t_(R) =10.2 min. The presence of cyclohexene is alsodetectable by ¹ H NMR (CDCl₃) of the solution: cyclohexene vinyl protonsat δ=5.64 ppm, eneone vinyl proton at δ=5.69 ppm.

The concentrate was diluted with hexanes (250 mL) and 3N HCl (150 mL).The two phase mixture was warmed to 40° C. until enol ether hydrolysiswas complete. The layers were separated and the organic layer was washedwith half saturated sodium bicarbonate (100 mL). The hexane phase had avolume of 291 mL, contained less than 5% ethanol by volume and assayedfor 92 mg/mL of enone.

The solution was concentrated to 100 mL under reduced pressure (100mm/15° C.). The batch was diluted with t-butanol (175 mL) andre-concentrated to 100 mL (100 mm/40° C.). The batch contained 260 mg/mLof the desired 7-β-methyl enone.

Step 5 Oxidative Cleavage

    ______________________________________                                         ##STR21##                                                                     ##STR22##                                                                    Materials          Amt           Mol  MW                                      ______________________________________                                        7-β-Methylcholest-4-ene-3-one                                                               300    g      0.75 398                                     t-Butanol (d = 0.786)                                                                            6.6    L                                                   Sodium carbonate   159    g      1.5  106                                     Sodium periodate   1550   g      7.2  213.9                                   Potassium permanganate                                                                           11.1   g      0.07 158                                     D. I. Water        14.2   L                                                   Diatomite          50     g                                                   Ethyl acetate (d = 0.902)                                                                        2.6    L                                                   Heptane (d = 0.684)                                                                              5.0    L                                                   conc. Hydrochloric acid                                                                          250    mL                                                  5% Aqueous NaCl    2.5    L                                                   Acetic acid (d = 1.049)                                                                          9.0    L                                                   ______________________________________                                    

In a 5 L roundbottom flask was charged D.I. water (4.93 L), sodiumperiodate (1.55 Kg) and potassium permanganate (11.1 g). The slurry wasstirred at 65° C. for 30 minutes to obtain complete solution.

To a solution of the enone (300 g) in t-butanol (4.60 L) was added asolution of sodium carbonate (159 g) in water (2.3 L). The two phasemixture was warmed to 65° C. The enone should be toluene, ethanol andcyclohexene free. (NOTE: Concentration of enone in organic layer isabout 56 mgL⁻¹.) The sodium periodate solution was added to the enonesolution over 3 h with rapid stirring, maintaining the reactiontemperature at 65° C. The slurry was aged at 65° C. for 2 h. Theperiodate solution was added via a heated addition funnel.

Carbon dioxide gas was evolved during the reaction. A slow additionensures controlled gas evolution. No exotherm was detected duringaddition. During the addition a purple/brown slurry was formed.

The reaction progress was monitored by HPLC. A 2 mL sample of thereaction mixture was cooled to 15° C. and filtered. The filtrate (0.1mL) was diluted to 10 mL with water/CH₃ CN (1:3). HPLC conditions YMCBasic 25 cm×4.6 mm, CH₃ CN, 0.01M H₃ PO₄ ; 90:10 isocratic flow=1.5mL/min, UV detection at 200 nm!; enone t_(R) =11.5 min, seco-acid t_(R)=5.5 min.

The reaction was considered complete when the starting enone was <0.5mg/mL. Water (3.0 L) was added and the slurry heated to reflux for 2 hto decompose any remaining KMnO₄ (color change from purple to brown) andto dissolve most of the solids precipitated on the vessel walls. Theresultant slurry was cooled to 15° C. and filtered through dicalite (50g). The vessel and cake were washed with t-butanol/water (1:2, 6.0 L).

The filter cake was assayed for seco acid by dissolving 200-400 mg ofcake with 50 mL water and 50 mL acetonitrile then filtering into thesample vial through diatomite to remove the small amount of orangemanganese solids. The filtrates (pH=9.0-10.5) were extracted withheptane (5.0 L).

Ethyl acetate (2.6 L) was added to the aqueous mixture and the pHadjusted to 2.5±0.3 by the addition of conc. HCl (250 mL). The aqueouslayer was removed.

The organic layer was washed with 5% aqueous brine (2×1.2 L). The ethylacetate solution was concentrated (150 mm.Hg, 30° C.) to approx 10%volume. Acetic acid (7.4 L) was added and the residual ethyl acetateremoved by concentration (100 mm.Hg, 60° C.) to <1% by volume (<0.5 area% by HPLC). The final volume was adjusted to 5.0 L by addition of aceticacid. Ethyl acetate removal was monitored by HPLC using the conditionsabove except the flow rate was 0.5 mL min⁻¹ and UV detection at 210 nm.Ethyl acetate t_(R) =7.4 min, acetic acid t_(R) =6.9 min. The aceticacid solution was used directly in the following step (ene-lactamformation).

Step 6 NH-Enelactam Formation

    ______________________________________                                         ##STR23##                                                                     ##STR24##                                                                    Materials      Amt             Mole MW                                        ______________________________________                                        Seco-acid      265    g        0.634                                                                              418                                       Ammonium Acetate                                                                             488    g        6.33 77.1                                      2,6-di-t-butyl-4-                                                                            5.3    g        0.024                                                                              220                                       methylphenol (BHT)                                                            D.I. Water     565    mL                                                      Acetic acid    833    mL                                                      ______________________________________                                    

To a solution of seco-acid in acetic acid (265 g in 5.3 L) obtained inthe previous step was added BHT (5.3 g) and ammonium acetate (488 g) at20° C. The slurry was warmed to a gentle reflux under a nitrogenatmosphere for 3 h. Complete solution was obtained at 30° C. Theinternal temperature was 120° C. at reflux. Color changed from yellow todark red/brown. Use of reduced amounts of acetic acid results in oilingof the product at the crystallization stage.

The reaction progress was monitored by HPLC. HPLC conditions SB Phenyl,CH₃ CN, 0.01M H₃ PO₄ ; isocratic 80:20 for 30 min, flow=1.5 mL/min, UVdetection at 190/200 nm! Retention times: ene-lactam t_(R) =9.4 min,seco acid t_(R) =5.3 min. UV detection was at 190 nm for reactionprogress and 200 nm for s.m. and product assay. The reaction wasconsidered complete when <0.05 A% seco acid remained, about 3-4 hrs.

The reaction mixture was cooled to 60° C. and water (398 mL) added over15 min. (NOTE: Addition of exactly 7.5% v/v water to the acetic acidsolution is important.) The solution was allowed to cool to 50° C. andseeded with ene-lactam (1.0 g). Crystallization occurred at 50° C. Theslurry obtained was aged at 50° C. for 1 h and then cooled to 0°-2° C.over 2 h.

The slurry was filtered and the light tan solid washed with 5:1 aceticacid/water (1.0 L).

Step 7 NH-Enelactam Recrystallization

    ______________________________________                                         ##STR25##                                                                                    Amt                                                           Materials       MW               Mole                                         ______________________________________                                        Enelactam       20     g         0.041                                                        400                                                           D.I. Water      17     mL                                                     Acetic acid     133    mL                                                     BHT             0.20   g         0.00091                                                      220                                                           ______________________________________                                    

To 20 g at 83 wt % enelactam was added 100 mL acetic acid whichcontained 200 mg of BHT. The slurry was warmed to 60° C. under anitrogen atmosphere to achieve dissolution, then cooled to 50° C. Acharge of 10 mL water was then added. The mixture was then cooled to 5°C. over 1.5 hrs, aged for one hour and then the solid filtered off.(NOTE: The solution at 50° C. should have started crystallizing beforecooling to 5° C.) The solution Kf after BHT addition was about 0.2-0.4%w/w.

The mother liquor amounts were monitored by HPLC. HPLC conditions SBPhenyl, CH₃ CN, 0.01M H₃ PO₄ ; isocratic 80:20 for 30 min, flow=1.5mL/min, UV detection at 200 nm! Retention times: ene-lactam t_(R) =9.4min. Sample 100 μL and dilute to 10 mL with acetonitrile.

The slurry was filtered and the light tan solid washed with 5:1 aceticacid/water (40 mL) at 5° C.

M.p. solvate is 112°-115° C. Pure m.p. is 175°-178° C., softens at 162°C.

Step 8 N-H Enelactam Reduction

    ______________________________________                                         ##STR26##                                                                     ##STR27##                                                                    Materials       Amount        Mol     MW                                      ______________________________________                                        Enelactam       1.02   g      .0026   339.6                                   Ethanol(punctilious)                                                                          100    mL                                                     BHT             2      mg                                                     5% Rhodium on carbon                                                                          200    mg      .097 mmol                                                                            103                                     ______________________________________                                    

BHT (2 mg) was dissolved in degassed ethanol (100 mL) and the solutiondegassed with nitrogen purge. The enelactam and 5% Rhodium on carbon(200 mg) were added and the slurry degassed for a further 30 minuteswith stirring. The resultant slurry placed under 250 psi of hydrogen ina stirred autoclave maintained at 30° C. The reaction progress wasmonitored by HPLC. HPLC conditions Zorbax® Phenyl, MeOH, H₂ O; 90:10isocratic, flow=1.0 mL/min, UV detection at 210 nm! ene-lactam t_(R)=min, 5-α lactam t_(R) =12.4 min, 5-β lactam t_(R) =15.0 min.

After 24 hours the mixture was removed from the hydrogenator and thecatalyst filtered off. Analysis of the solution by HPLC shows a 1:264mixture of 5-β:5-α product. The solution was concentrated to give theproduct as a white solid (m.p. 188°-190° C., 90% yield), 300 MHz NMR (H¹CDCl₃): 5.96(1H,brs), 3.05(1H,dd,J=12.3,3.5 hz), 2.38(2H,m), 2.0(1H,m),1.75(3H,m), 1.60-0.7(34H,m), 0.67(3H.s); (C¹³ CDCl₃) 172.2, 59.6, 56.8,55.3, 52.0, 44.1, 42.6, 40.1, 39.5, 37.9, 36.2, 35.7, 35.2, 35.1, 33.6,28.7, 28.6, 28.0, 27.8, 23.9, 23.0, 22.8, 22.6, 21.8, 18.9, 12.5, 11.5.

If an N-alkyl compound of formula II is desired, lactam 8 may beN-alkylated as illustrated by Example 2 shown below.

EXAMPLE 2 Methylation of 7β-methyl-4-aza-5α-cholestan-3-one

    ______________________________________                                         ##STR28##                                                                     ##STR29##                                                                    Materials       Amount         Mol  MW                                        ______________________________________                                        NH Lactam       3.0    Kg      7.47 401.6                                     Methyl chloride 453    g       8.96 50.5                                      KOH/Alumina 1:1!                                                                              3.0    Kg      22.8 56                                        BnMe.sub.3 NCl  150    g       0.81 185.7                                     Toluene (d = 0.867)                                                                           14.0   L                                                      ______________________________________                                    

A 5 gallon autoclave was charged with a slurry of lactam (3.0 Kg), BnMe₃NCl (150 g) and potassium hydroxide on alumina (1:1, 3.0 Kg) in toluene(12 L) at room temperature. Methyl chloride (453 g) was introduced at20° C. with slow stirring. The slurry was heated to 65° C. with slowstirring and aged for 1 h. An exotherm at 52° C. of about 3° C. wasnoted as a spike on the temperature recorder.

The reaction progress was monitored by HPLC. HPLC conditions Zorbax® SBphenyl, CH₃ CN, 0.01M H₃ PO₄ ; 90:10 isocratic, flow=1.5 mL/min, UVdetection at 200 nm! lactam t_(R) =12.4 min, IV-a t_(R) =15.0 min. 25 μLSample of toluene layer was diluted to 2 mL with acetonitrile. Thereaction was monitored until complete conversion was obtained (>99.95%).The reaction was complete in <60 min at 60° C.

The reaction mixture was cooled to 20° C. and purged with nitrogen (4X)to remove any excess MeCl. The toluene solution was filtered throughSolka Floc™ diatomaceous earth (100 g) and the vessel and cake washedwith toluene (2 L). The combined filtrates were concentrated at 100 mm.Hg and 20°-30° C. to a residual oil. The oil should be homogeneous inheptane (10 mLg-1) without any cloudiness.

The oil was assayed for toluene by G.C. oven temp 35° C. isothermal. Theproduct (100 mg) was dissolved in methanol (0.5 mL) and 1 μL injected.Toluene t_(R) =4.4 min, methanol t_(R) =2.7 min.

The oil was kept under vacuum until the solvent level was <2%. The oilwas poured into a glass tray and seeded with IV-a (1.25 g) and allowedto stand in vacuo (20 mm.Hg) overnight.

The resulting solid was cut into blocks and broken up in a WARINGblender containing 2° C. water (10 L) to a particle size of <50 μm. Theslurry was filtered, washed with water (5.0 L) and dried in a nitrogenstream overnight. Yield of product=3.0 kg, 97%.

The process of the present invention can also be used to directly reducean N-alkylated enelactam of formula I as illustrated by Example 3.

EXAMPLE 3 Preparation of 4,7β-dimethyl-4-aza-5α-cholestan-3-one

    ______________________________________                                         ##STR30##                                                                     ##STR31##                                                                    Materials       Amount         Mol  MW                                        ______________________________________                                        Enelactam       1900.0  g      4.75 399.64                                    Ethanol(punctilious)                                                                          22      L                                                     5% Rhodium on carbon                                                                          380     g      0.18 103                                       Hydrogen        250     psi                                                   Celite          100     g                                                     Hexane          4.0     L                                                     ______________________________________                                    

Enelactam (1900.0 g) was dissolved in ethanol (8.0 L) and the solutiondegassed with nitrogen purge for 18 h. 5% Rhodium on carbon (380 g) wasadded and the slurry degassed for a further 30 minutes with stirring.The resultant slurry was charged to a 5 gallon stirred autoclave.

A further charge of degassed ethanol (4.0 L) was used to rinse thestarting material and catalyst into the autoclave. The hydrogenation wasperformed at 30° C. and 250 psi hydrogen pressure for 18 h. Typically<4% ene-lactam remains after 18 h.

The reaction progress was monitored by HPLC, YMC-basic, CH₃ CN, 0.1M H₃PO₄ ; 1.5 mL/min, λ=210 nm!. Retention times: Enelactam 16.1 min,trans-lactam 13.8 min, cis-lactam 13.1 min, 7-des methyl trans-lactam12.4 min. Samples for HPLC analysis were removed without introducingoxygen into the system.

The hydrogenation mixture was filtered through Celite (100 g). Ethanol(8.0 L) was used to rinse the autoclave and wash the cake. The Celitewas washed with ethanol (2000 mL).

The combined colorless filtrate was concentrated to residue at 75 mm.Hexane (4.0 L) was added, concentrated to residue and assayed forproduct. Analysis of the solution by HPLC shows a 1:500 mixture of5-β:5-α product. The assay yield was 98%. The crude product containedunreacted ene-lactam (1.8%), 7-des methyl trans-lactam (<0.1%) andcis-lactam (<0.2%). The hydrogenation also produced 0.07% over-reducedproduct which lacks the lactam carbonyl oxygen.

The resulting oil was chromatographed on silica gel (17 kg, 230-400mesh) eluting with 1:3 v/v ethyl acetate:hexane (100 L) followed by 3:1v/v ethyl acetate:hexane (140 L). The fractions containing the 5α/βproducts were combined and concentrated under vacuum. The resultant oilwas seeded with 5α product (1.0 g) and allowed to crystallize over 5days. The resulting solid was ground in a mortar and pestle to give4,7β-dimethyl-4-aza-5α-cholestan-3-one (1.53 Kg) as a white, low meltingcrystalline solid, m.p. 58°-62° C., 300 MHz ¹ H NMR (H¹ CDCl₃): 3.02(1H,dd, J=12.7, 3.6), 2.92(3H, s), 2.43(2H, m), 2.01(1H, dt, J=12.3, 3.2),1.92(1H, dt, J=12.7, 4.0), 1.89-1.70(3H,m), 1.58(1H, m), 1.52(1H,m),1.41-0.96(17H, m), 1.05(3H, d, J=6.3), 0.92(3H, d, J=6.3), 0.87(3H, d,J=6.7), 0.86(3H, d, J=6.7), 0.84(3H, s), 0.81(1H, m), 0.68(3H, s), 75MHz ¹³ C NMR (C¹³ CDCl₃): 170.6, 64.7, 56.8, 55.2, 52.6, 44.0, 41.7,40.1, 39.5, 36.1, 35.9, 35.8, 35.7, 33.1, 29.1, 28.6, 28.0, 27.7, 23.8,23.2, 22.8, 22.5, 21.7, 18.8, 12.6, 12.4.

EXAMPLE 4 Preparation of 7β-methyl-4-aza-5β-cholestan-3-one

    ______________________________________                                         ##STR32##                                                                     ##STR33##                                                                    Materials       Amount   Mol      MW                                          ______________________________________                                        Enelactam       333 mg   0.83 mmol                                                                              399.6                                       Trifluoroacetic acid                                                                           3 mL                                                         Di-t-butylmethylsilane                                                                        260 mg                                                        ______________________________________                                    

To 333 mg of enelactam (0.83 mmol) in 3 mL of trifluoroacetic acid wasadded 260 mg di-t-butylmethylsilane (1.64 mmol) and the mixture heatedto reflux for about 2 hours until no enelactam remains. The mixture wascooled, concentrated to an oil, dissolved in hexane and washed withwater twice.

Analysis of the mixture by HPLC showed a 90:1 ratio of 5-β:5-α product.Chromatography on silica using ethyl acetate gave the product as a whitesolid (m.p. 90°-94° C., 87% yield).

As in preparation of the α-reduction product, the process of thisinvention can be used to produce 5β-reduction products of N--Henelactams which can be subsequently N-alkylated as in Example 2 or todirectly reduce N-alkylated enelactams as in Example 3.

EXAMPLE 5 Preparation of4,7β-dimethyl-4-aza-5β-16β-hydroxy-androst-3-one

    ______________________________________                                         ##STR34##                                                                     ##STR35##                                                                    Materials       Amt.           mmole MW                                       ______________________________________                                        Enelactam (100 wt %)                                                                          2.0    g       6.3   317.5                                    TFA             20     mL                                                     Me(tBu).sub.2 SiH                                                                             5      g       31.5  158                                      EtOH            20     mL                                                     KOH             1.76   g       31.5  56                                       ______________________________________                                    

To the enelactam alcohol (2.0 g, 6.3 mmol) in TFA (20 mL) was addedMe(tBu)₂ SiH and heated to 60°-70° C. until less than 1% remained.

The reaction was monitored by HPLC. YMC-ODS-H80, CH₃ CN:0.01% H₃ PO4:gradient elution from 60:40 to 90:10 in 15 minutes, flow=1.5 mL/min, UVdetection at 210 nm. Enelactam-16-β-OH R_(T) =8.4 min, lactam-16-β-OHR_(T) =3.7 min, lactam-16-α-OH R_(T) =3.9 min intermediatetrifluoroacetate, R_(T) =15.6 min.

The reaction mixture was cooled to RT and concentrated in vacuo. The oilwas dissolved in 20 mL ethanol and 1M KOH (31 mL) added. The mixture washeated to 50° C. and aged until the trifluoroacetate was gone. Aftercooling to RT, 50 mL toluene was added and the layers separated. HPLCassay shows a 1:30 ratio of 5-α:5-β reduction isomers. The toluene layerwas washed 2×50 mL water and then solvent switched to acetonitrile (10mL), cooled to 0° C. and filtered off a white solid. 300 MHz ¹ HNMR(CDCl₃): 4.35 (1H, m), 3.0 (1H, dd, J=5.6, 2.8 Hz), 2.90 (3H, s), 2.4(1H, br s), 2.3 (2H, m), 0.90-1.75(m, 25H). 75 MHz ¹³ C NMR (CDCl₃):171,1, 71.7, 64.9, 54.2, 50.7, 42.7, 41.3, 41.2, 40.2, 39.1, 34.6, 33.9,31.7, 31.4, 31.0, 28.4, 22.2, 21.7, 21.4, 19.1.

EXAMPLE 6 Preparation of 7β-methyl-4-aza-5β-16β-phenoxy-androst-3-one##STR36##

Starting with the enelactam above, the title compound is preparedaccording to the procedures of Example 4.

EXAMPLE 7 Preparation of4,7β-dimethyl-4-aza-5β-16β-hydroxy-androst-3-one (Rhodium Hydrogenation)

    ______________________________________                                         ##STR37##                                                                     ##STR38##                                                                    Materials         Amt.          mmole MW                                      ______________________________________                                        Enelactam (100 wt %)                                                                            1.150  g      3.62  317.46                                  5% Rh/C           0.640  g                                                    95% Ethanol       17     mL                                                   Solka Floc ™ diatomaceous earth                                                              5      g                                                    DI water          30     mL                                                   ______________________________________                                    

The enelactam alcohol (1.15 g) was dissolved in 95% ethanol (12 mL) anddegassed with a nitrogen purge for 15 min. To this solution was added of5wt % Rh/C (0.64 g) and the slurry transferred to a stirred autoclaveusing 2.5 mL additional EtOH as a rinse. The mixture was placed under 40psi hydrogen and heated to 30° C. for 4 h and then heated to 50° C.until <0.01% starting material remained.

The reaction was monitored by HPLC. SB phenyl CH₃ CN: 0.01% H₃ PO₄ :gradient elution from 45:55 for 10 min then gradient elution to 90:10 in15 minutes, flow=1.5 mL/min, UV detection at 210. Enelactam-16-β-OHR_(T) =8.4 min, 5-b-lactam-16 β-OH R_(T) =3.7 min, 5-a-lactam-16-α-OH3.9 min.

The batch was removed from the autoclave and cycled through a pad ofSolka Floc™ diatomaceous earth until the rhodium was removed. Anadditional 15 mL of ethanol was used to wash the product from the filtercake. The combined filtrates were then re-filtered through a 0.2 μmin-line filter and concentrated to about 5 mL ethanol. HPLC assay showsa 250:1 ratio of 5-α:5-β reduction isomers. Water was slowly added untilthe cloud point was reached (20 mL), seeded with 10 mg lactam and aged20 min. The slurry was then cooled to 0° C. and filtered. The productwas obtained as a white solid. The filtrate and washes contains 3% ofproduct.

300 MHz ¹ H NMR(CDCl₃): 4.35 (1H, m), 3.0 (1H, dd, J=9.5, 3.2 Hz), 2.89(3H, s), 2.4-2.2 (2H, m), 0.90-1.75(m, 25H).

75 MHz ¹³ C NMR (CDCl₃): 170.9, 71.8, 64.8, 53.9, 52.7, 50.6, 41.7,41.5, 40.7, 39.2, 36.0, 35.54, 35.50, 32.9, 29.3, 29.0, 22.9, 21.4,19.5, 12.6.

EXAMPLE 8 Preparation of4,7β-dimethyl-4-aza-5β-16β-phenoxy-androst-3-one ##STR39##

Starting with the 16-phenoxy-4,7b-dimethyl-4-aza-androst-5-en-3-oneabove and following the procedures of Example 4, the title compound isprepared.

EXAMPLE 9

According to the procedures outlined in Examples 1-8, the followingcompounds of structural formula below are prepared from thecorresponding ene-lactam.

    ______________________________________                                         ##STR40##                                                                    Compound      R       R.sup.1  A                                              ______________________________________                                        30            H       H        OH                                             31            Me      H        OH                                             32            Me      Me       OMe                                            33            H       Me       (CH(CH.sub.3).sub.2)                           ______________________________________                                    

EXAMPLE 10

According to the procedures outlined in Examples 1-8, the followingcompounds of structural formula below are prepared from thecorresponding ene-lactams

    ______________________________________                                         ##STR41##                                                                    Compound    R      R.sup.1 A                                                  ______________________________________                                        40          H      H       OH                                                 41          H      Me                                                                                     ##STR42##                                         42          Me     Me      OMe                                                43          Me     Me                                                                                     ##STR43##                                         44          H      Me                                                                                     ##STR44##                                         45          Me     Me                                                                                     ##STR45##                                         ______________________________________                                    

EXAMPLE 11

According to the procedures outlined in Examples 1-8, the followingcompounds of structural formula below are prepared from thecorresponding ene-lactams

    ______________________________________                                         ##STR46##                                                                    Compound      R        R.sup.1  A                                             ______________________________________                                        50            H        Me       CH(CH.sub.3).sub.2                            51            H        Me       OH                                            52            Me       Me       OMe                                           53            Me       Me       OAc                                           54            H        Me       CO.sub.2 H                                    ______________________________________                                    

EXAMPLE 12

According to the procedures outlined in Examples 1-8, the followingcompounds of structural formula below are prepared from thecorresponding ene-lactams

    ______________________________________                                         ##STR47##                                                                    Compound    R      R.sup.1 A                                                  ______________________________________                                        60          H      Me                                                                                     ##STR48##                                         61          Me     Me                                                                                     ##STR49##                                         62          H      Me                                                                                     ##STR50##                                         63          H      Me      OCH.sub.3                                          ______________________________________                                    

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations, and modifications, as come within thescope of the following claims and its equivalents.

What is claimed:
 1. A process for the stereoselective reduction of a Δ-5 steroidal enelactam of the formula I; ##STR51## wherein: Z is ##STR52## R is selected from H and C₁ -C₅ alkyl; R¹ is selected from C₁₋₅ alkyl and phenyl; andA is any synthetically feasible substituent and which comprises(b) refluxing said Δ-5 steroidal enelactam in an ionizing medium in the presence of a trialkylsilane of the formula (R²)₃ SiH, wherein R² is selected from C₁₋₆ alkyl and phenyl; provided that when Z is ##STR53## and R is selected from H and C₁₋₅ alkyl, A is not C₁₋₁₀ alkyl.
 2. The process of claim 1 wherein A is selected from:--H, protected hydroxy, acetoxy, hydroxy, carboxy, protected amino, amino, C₁₋₁₀ alkyl, substituted or unsubstituted C₁₋₁₀ alkynyl, aryl-substituted C₁₋₁₀ alkyl, aryl, substituted aryl, aryl carbamoyl-substituted C₁₋₁₀ alkyl, C₁₋₁₀ alkylcarbonyl, arylcarbonyl, ether-substituted C₁₋₁₀ alkyl, keto-substituted C₁₋₁₀ alkyl, heteroaryl-substituted C₁₋₁₀ alkyl, carboxylic ester, carboxamide, carbamoyl, substituted N-phenylcarboxamide ureido, C₁₋₁₀ alkylureido, C₁₋₁₀ alkylureido C₁₋₅ alkyl, substituted or unsubstituted arylureido, substituted or unsubstituted arylureidoC₁₋₅ alkyl, C₁₋₁₀ alkanoyloxyC₁₋₂ alkyl, C₁₋₁₀ alkylcarbonylamino, alkanoylamidoalkyl, alkoxy, alkylthio, arylthio and substituted and unsubstituted aryl oxy.
 3. The process of claim 2 wherein(a) protected hydroxy is selected from: dimethyl-t-butyl silyloxy, trimethylsilyloxy, tri-ethylsilyloxy, tri-isopropylsilyloxy, and triphenylsilyloxy; (b) protected amino is acetylamino; (c) C₁₋₁₀ alkyl is selected from methyl, ethyl, propyl, butyl, pentyl, 1,5-dimethylhexyl, 6-methylhept-2-yl, and 1-methyl-4-isopropylhexyl; (d) substituted or unsubstituted C₁₋₁₀ alkynyl is selected from: phenylmethylenyl chlorophenylmethylenyl ethoxycarbonylphenylmethylenyl, carboxyphenylmethylenyl (((1,1-dimethylethyl) amino) carbonyl)phenylmethylenyl trimethoxyphenyl methylenyl, methoxyphenylmethylenyl, methylsulfonylphenylmethylenyl, biphenylmethylenyl, nitrophenylmethylenyl, aminophenylmethylenyl, acetylaminophenylmethylenyl, pivaloylaminophenylmethylenyl, phenoxyphenylmethylenyl, 2-imidazolyl methylenyl, and 2-thiazolylmethylenyl; (e) aryl substituted C₁₋₁₀ alkyl is selected from omega-phenylpropyl, and 1-(chlorophenoxy)ethyl; (f) aryl is selected from phenyl, pyridinyl and pyrimidinyl; (g) substituted aryl is selected from phenyl, pyridinyl and pyrimidinyl substituted with one to three substituents independently selected from:(1) --H, (2) --OH, (3) --CH₃, (4) --OCH₃, (5) --S(O)_(n) --CH₃, wherein n is selected from 0, 1, and 2, (6) --CF₃, (7) halo, (8) --CHO, (9) CN, and (10) --NHR⁷, wherein R⁷ is selected from:--H, --C₁₋₈ alkyl, --C₁₋₆ alkylcarbonyl, --C₁₋₆ alkylsulfonyl, and --C₁₋₆ alkoxycarbonyl, (h) aryl carbamoyl substituted C₁₋₁₀ alkyl is 2-(4-pyridinylcarbamoyl)ethyl; (i) C₁₋₁₀ alkylcarbonyl is isobutylcarbonyl; (j) arylcarbonyl is phenylcarbonyl; (k) ether-substituted C₁₋₁₀ alkyl is selected from 1-methoxy-ethyl, and 1-ethoxy-ethyl; (l) keto-substituted C₁₋₁₀ alkyl is selected from: 1-keto-ethyl, ketomethyl, 1-ketopropyl, and ketobutyl; (m) heteroaryl-substituted C₁₋₁₀ alkyl is omega-(4-pyridyl)-butyl; (n) carboalkoxy is C₁₋₁₀ alkylcarboxy selected from carbomethoxy and carboethoxy; (o) carboxamido is selected from N,N-diisopropyl carboxamido, N-t-butyl carboxamido, N-(hydroxyphenyl) carboxamido, N-phenylcarboxamido, N-(aminophenyl) carboxamido, N-(carbomethoxy)phenyl carboxamido, N-(methoxycarboxy) phenyl carboxamido, N-acetamidophenyl-N-acetyl-carboxamido, N-acetamidophenyl-carboxamido, N-pivalamidophenyl carboxamido, N-isobutyramidophenyl carboxamido, N-(methyl),N-(diphenylmethyl) carboxamido, and N-(diphenylmethyl)-carboxamido; (p) carbamoyl is selected from t-butylcarbamoyl and isopropylcarbamoyl; (q) substituted N-phenylcarboxamido wherein the phenyl is substituted with 1 to 2 substituents selected from ethyl, methyl, trifluoromethyl, --F, --Cl, --Br, and --I; (r) C₁₋₁₀ alkanoyloxyC₁₋₂ alkyl is selected from acetyloxymethyl, trimethylacetyloxymethyl, and (2-ethylhexanoyloxy)methyl, (s) ureido is t-butylcarbonylamino ureido; (t) C₁₋₁₀ alkylureido is selected from: N-isopropylureido, and allylureido; and C₁₋₁₀ alkylureido C₁₋₅ alkyl, is selected from: N-t-butylureidomethyl, N-n-propylureidomethyl, and N-n-octylureidomethyl; (u) substituted or unsubstituted arylureido is selected from: N-(fluorophenyl)ureido, and N-(methoxyphenyl)ureido; and substituted or unsubstituted arylureidoC₁₋₅ alky is selected from: N-(ethylphenyl) ureidomethyl, N-(chlorophenyl) ureidomethyl, N-phenylureidomethyl, N-(dichlorophenyl) ureidomethyl, N-naphth-2-yl)ureidomethyl, N-thiazol-2-ylureidomethyl, N-thien-2-ylmethylureidomethyl, and 2-(ethoxyphenyl)ureidomethyl (v) C₁₋₁₀ alkylcarbonylamino is t-butylcarbonylamino; (w) alkanoylamidoalkyl is selected from: trimethylacetamidomethyl, carbomethoxyoctanoylamidomethyl, (isobutylphenyl) propionamidomethyl, 8-carboxyoctanoylamidomethyl, bromohexanoylamidomethyl, hydroxydodecanoyl amidomethyl, 4-nitrophenylprionamidomethyl, isopropylthioacetamidomethyl, benzyloxyacetamidomethyl, carbomethoxyacetamidomethyl, triphenylprionamidomethyl, cyclohexylacetamidomethyl, methylcyclohexanecarboxamidomethyl, (3-hydroxy-4,4,4-trichlorobutyramido)methyl, and phenylthio-acetamidomethyl; (x) alkyloxy is C₁₋₈ alkyl ether optionally substituted with hydroxy, halo, C₁₋₈ alkoxy, C₁₋₆ alkenyl, or aryl, (y) alkylthio is selected from: C₁₋₈ alkylthio and C₁₋₈ alkylthio substituted with phenyl; and arylthio is phenylthio; and (z) substituted and unsubstituted aryl oxy is selected from thiophenoxy, biphenyloxy, acetamidophenoxy, (3-pyridyl)oxy, chlorophenyloxy, methylphenyloxy, phenyloxy, hydroxyphenyloxy, methylsulfonylphenyloxy and pyrimidinyloxy.
 4. The process for the stereoselective reduction of claim 1 wherein Z is: ##STR54## and A is selected from carboxyl and hydroxyl.
 5. The process for the stereoselective reduction of claim 4 wherein R is selected from H and methyl and R¹ is methyl.
 6. The process for the steroselective reduction of claim 1 wherein Z is: ##STR55## and A is selected from hydroxyl and protected hydroxyl.
 7. The process for the stereoselective reduction of claim 6 wherein R is selected from H and methyl and R¹ is methyl.
 8. The process for the stereoselective reduction of claim 1 wherein Z is: ##STR56## and A is selected from alkyoxy and aryloxy.
 9. The process of claim 8 wherein R is selected from H and methyl and R¹ is methyl.
 10. The process for the stereoselective reduction of claim 1 wherein Z is: ##STR57## A is C₁₋₁₀ alkyl.
 11. The process of claim 4 where R is selected from H and methyl.
 12. The process of claim 1 in which the Δ-5 steroidal enelactam is refluxed in an ionizing medium with a trialkylsilane to preferentially yield the 5β-azasteroid.
 13. The process of claim 12 where the ionizing medium is trifluoroacetic acid.
 14. The process of claim 13 where the trialkylsilane is selected from di-t-butylmethylsilane and tri-t-butylsilane. 